5-HT mechanisms are implicated in common age-associated diseases, including treatment-resistant mood disorders. Our previous work indicates that the neurotrophin BDNF promotes 5-HT axonal growth in the adult brain. However, 5-HT neurons may lose the ability to respond to BDNF in aging. The present proposal examines whether age-associated dysfunction of 5-HT neurons in the rat forebrain may be caused by deficient neurotrophic (e.g., BDNF) support mechanisms. Specific Aim 1 of this proposal examines whether 5-HT neurons lose their structural plasticity with age, as manifested by an impaired regenerative response to injury and a reduced responsiveness to BNDF. Specific Aim 2 examines whether their is an endogenous loss of BDNF availability/signal transduction in 5-HT neurons during aging. Finally, Specific Aim 3 uses mutant BDNF-deficient mice to examine whether endogenous BDNF expression and signal transduction are necessary for the normal integrity and plasticity of 5-HT neurons adulthood 44 and aging. The goal of this research is to gain a better understanding of the molecular interactions between 5-HT neurons and their trophic support mechanisms in aging and whether a deficiency in this interaction contributes to an age-associated pathophysiology of the 5-HT system. It is hoped that this knowledge will facilitate the design of more effective therapeutic approaches to treat age-related psychiatric diseases that may be associated with dysfunction of 5-HT neurons.